We have participated in the generation of a high resolution SNP haplotype map (1 SNP/Kb), which has provided tagging SNPs that can be used as a rapid means for detection of MHC disease associations. Further, we participated in another study in which two related MHC haplotypes that associate with distinct human diseases were compared. Such studies have resulted in a more thorough characterization of the MHC than any other genetic locus of its size in humans. Full sequence analyses of two non-human primate KIR haplotypes were generated providing direct evidence for the rapid evolution of this locus, and a novel, ancestral KIR gene in primates has been discovered. Comparisons of the rhesus monkey, common chimpanzee, and human KIR haplotypes were performed and indicated species-specific diversification of the KIR locus, apparently in a manner that conforms to the MHC of that species. In a second study, we identified the ancestral KIR lineage (termed KIR3DL0) from which all other KIR genes throughout the primate order appear to have been derived. We have begun to use population studies as a means to enhance and better understand disease associations with the various genes we study (with emphasis on the MHC and KIR loci). Extensive HLA class I diversity was observed amongst seven indigenous Cameroonian populations, in a region where broad diversity of HIV-1 has also been described, emphasizing the challenges in development of a T cell-based vaccine. We have also shown a lack of evidence for active diversification of the MICA gene after racial separation, indicating an evolutionary history distinct from that of the classical HLA genes. Comparisons of KIR genes across primate species have demonstrated the rapid evolution of this receptor family, possibly more rapid than their MHC class I ligands. The extensive diversity of the HLA and KIR gene loci and the central role of their interactions in modulating immune responses are expected to favor the co-evolution of genotypic combinations of these two loci in order to maintain appropriate levels of functional interaction. Comparative genetic studies across primate species as well as disease studies have indeed shown evidence of HLA-KIR co-evolution. However, direct evidence from human population studies, which could pinpoint receptor-ligand combinations that are major factors in their co-evolution, has been lacking. Significant correlations between frequencies of specific KIR genes and HLA alleles encoding their corresponding ligands would support the hypothesis that these unlinked loci are co-evolving. To assess evidence for co-evolution of KIR and HLA class I at the population level, we genotyped 1642 unrelated individuals from 30 geographically distinct populations throughout the world. Each individual was tested for the presence/absence of specific KIR genes and their ligands. Strong negative correlations were observed between the presence of activating KIR genes and their corresponding HLA ligand groups across populations, especially KIR3DS1 and its putative HLA-B Bw4-80I ligands (r=-0.66, p=0.038). In contrast, weak positive relationships were observed for the various inhibitory KIR and their ligands. Opposing trends with distance from East Africa for frequencies of activating KIR genes and their corresponding ligands suggest a balance between selection on HLA and KIR loci. Taken together, the data provide population-level evidence for the evolution of the KIR gene cluster due to selection pressure favoring frequencies of activating KIR that suit the locale-specific HLA repertoire.